The present invention relates generally to pharmaceutical formulations and methods of use thereof, More particularly, the invention relates to pharmaceutical formulations of resveratrol (3,5,4xe2x80x2-trihydroxystilbene) that are useful, for example, in the prevention and treatment of skin conditions associated with inflammation, sun damage and aging. The invention finds utility in the fields of drug delivery, medicine and pharmacology.
It has been noted that there are a number of biologically active phenolic compounds present in wine, particularly red wine. Such compounds include, for example, catechin, epicatechin, quercetin, rutin, trans-resveratrol, cis-resveratrol, cis-resveratrol glucoside and trans-resveratrol glucoside. See, e.g., Goldberg et al. (1996) Anal. Chem. 68:1688-1694. These compounds have been shown to protect low-density lipoproteins against oxidation. The resveratrol isomers, in particular, have been found to promote vascular relaxation through the generation of nitric oxide by the endothelium, and to modulate eicosanoid synthesis in a manner that suggests use in preventing coronary heart disease. Id. at pp. 1688-89). This discovery appears to explain the studies demonstrating that moderate consumption of red wine tends to have a protective effect against heart disease. Bertelli et al. (1995) Inst. J Tiss. Reac. XVII(1):1-3. 
Resveratrol (3,5,4xe2x80x2-trihydroxystilbene) has been identified as a constituent not only of grape skins (Soleas et al. (1995) Am. J. Enol. Vilic. 46(3):346-352) but has also been found to be present in ground nuts, eucalyptus, and other plant species. Goldberg et al. (1995), Am. J Enol. Vilic. 46(2):159-165. A great deal of interest has been focused on the compound""s antifungal activity and its correlation with resistance to fungal infection. Id. at 159. Resveratrol may be obtained commercially (typically as the trans isomer, e.g. from the Sigma Chemical Company, St. Louis, Mo.), or it may be isolated from wine or grape skins, or it may be chemically synthesized. Synthesis is typically carried out by a Wittig reaction linking two substituted phenols through a styrene double bond, as described by Moreno-Manas et al. (1985) Anal. Quim 81:157-61 and subsequently modified by others (Jeandet et al. (1991) Am. J. Enol. Vilic. 42:41-46; Goldberg et al. (1994) Anal. Chem. 66: 3959-63).
There are more studies concerning trans-resveratrol than the cis isomer;
however, the cis isomer appears to be equally important from a biological standpoint. Numerous uses have been proposed and evaluated for the resveratrol isomers. Jang et al. (1997) Science 275:218-220, show that resveratrol has cancer chemopreventive activity in assays representing three major stages of carcinogenesis.
That is, the authors found that the compound: (1) acted as an antioxidant and antimutagen and induced phase II drug-metabolizing enzymes; (2) mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase; and (3) induced human promyelocytic leukemia cell differentiation. In addition, as noted above, resveratrol has been extensively studied for its correlation to the cardiovascular utility of red wine. See, e.g., Bertelli et al., supra; Pace-Asciak et al. (1995), Clinica Chimica Acta 235:207-2191; and Frankel et al. (Apr. 24, 1993), The Lancet 341:1104. Neurologic uses have also been proposed (Lee et al. (1994), Society for Neuroscience Abstracts 20(1-2):1648).
To date, however, topical administration of resveratrol is unknown. The present invention is premised on the unexpected finding that topical administration of resveratrol is extremely effective in preventing or treating certain skin conditions, disorders and diseases, e.g., skin conditions associated with inflammation, skin damage associated with exposure to the sun, and the effects of natural aging. It has in addition been discovered that administration of resveratrol in the form of a microemulsion is a particularly effective mode of administering the active agent.
In addition, resveratrol has found to be useful as a cancer chemopreventive agent. Known cancer chemopreventive agents include nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin, aspirin, piroxicam, and sulindac, all of which inhibit cyclooxygenase, abbreviated hereafter as COX. A COX inhibitory activity is important in cancer chemoprevention because COX catalyzes the conversion of arachidonic acid to proinflammatory substances, such as prostaglandins, which can stimulate tumor cell growth and suppress immune surveillance. Plescia et al. (1975) Proc. Natl. Acad. Sci. U.S.A. 72:1848; Goodwin (1984) Am. J Med. 77:7. In addition, COX can activate carcinogens to forms that damage genetic material. Zenser et al. (1983), J. Pharmacol Exp. Ther. 227:545; Wild et al. (1987) Carcinogenesis 8:541. Investigators have searched for new cancer chemopreventive agents by evaluating hundreds of plant extracts for a potential to inhibit COX. An extract derived from Cassia quinquatngilata Rich. (Leguminosae) was identified as a potent COX inhibitor, and on the basis of bioassay-guided fractionation, trans-resveratrol was identified as the active compound. See Mannila et al. (19983) Phytochemistry 33:813, and Jayatilake et al. (1993), J. Nat. Prod. 56:1805.
Accordingly, it is a primary object of the invention to address the above-mentioned needs in the art by providing a method for preventing or treating certain skin conditions, disorders and diseases.
It is another object of the invention to provide such a method by administering to a patient a formulation comprising an active agent selected from the group consisting of resveratrol, pharmacologically acceptable salts, esters, amides, prodrugs and analogs thereof, and combinations of any of the foregoing.
It is another object of the invention to provide such a method wherein the formulation is administered topically.
It is still another object of the invention to provide such a method wherein the skin condition, disorder or disease is associated with inflammation.
It is yet another object of the invention to provide such a method in the context of preventing or treating skin-related sun damage and/or the effects of natural aging on the skin.
It is an additional object of the invention to provide such a method in the context of preventing skin cancer.
It is a further object of the invention to provide such methods by administering resveratrol in stereoisomerically pure form, i.e., in either the cis or the trans form.
It is still a further object of the invention to provide novel pharmaceutical formulations comprising an active agent selected from the group consisting of resveratrol, pharmacologically acceptable salts, esters, amides, prodrugs and analogs thereof, and combinations of any of the foregoing, in combination with a pharmaceutically acceptable carrier.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one embodiment, then, a method is provided for preventing or treating certain skin conditions, disorders or diseases comprising administering to the susceptible or affected individual, preferably by application to the individual""s skin, a pharmaceutical composition comprising a therapeutically effective amount of an active agent selected from the group consisting of resveratrol, pharmacologically acceptable salts, esters, amides, prodrugs and analogs thereof, and combinations of any of the foregoing. Generally, the active agent will be cis-resveratrol, trans-resveratrol, or a complex in which one or more of the compounds"" hydroxyl groups are conjugated to a mono- or di-saccharide, e.g., cis-resveratrol glucoside, trans-resveratrol glucoside, etc. However, as will be appreciated by those skilled in the art, and as discussed in detail elsewhere herein, other forms of the active agents may also be used. The skin condition, disorder or disease may be, for example, psoriasis, contact dermatitis (including irritant contact dermatitis and allergic contact dermatitis), atopic dermatitis (also known as allergic eczema), actinic keratosis, keratinization disorders (including eczema), epidermolysis bullosa diseases (including penfigus), exfoliative dermatitis, seborrheic dermatitis, erythemas (including erythema multiforme and erythema nodosum), damage caused by the sun or other light sources, discoid lupus erythematosus, dermatomyositis, skin cancer, effects of natural aging and the like.
In another embodiment, a pharmaceutical formulation is provided comprising an active agent as described above, with cis-resveratrol, trans-resveratrol, and conjugates of cis-resveratrol or trans-resveratrol with mono- or di-saccharides preferred. The formulation is preferably for topical administration, and thus also comprises a pharmaceutically acceptable topical carrier selected to correspond to the particular formulation type, e.g., ointment, lotion, cream, microemulsion, gel, oil, solution, or the like. The formulation may also contain one or more additional active agents and/or additives such as solubilizers, skin permeation enhancers, opacifiers, preservatives (e.g., anti-oxidants), gelling agents, buffering agents, surfactants, emulsifiers, emollients, thickening agents, stabilizers, humectants, colorants, fragrance, and the like. Inclusion of solubilizers and/or skin permeation enhancers is particularly preferred.